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What Makes Some Genes Disrupt Brain Development?

January 27, 2014

Daniel Weinberger, M.D.

From The Quarterly, Spring 2014

“It is now generally believed that an illness like schizophrenia is caused by many hundreds of genetic errors,” says Daniel Weinberger, M.D., from his office at the Lieber Institute for Brain Development at the Johns Hopkins University School of Medicine. The evidence, he says, is actually more intriguing than that. Across the human population, there may be many different genes whose malfunction can potentially contribute to pathology in the disease. But in any specific individual, “It may be that only three or four genes aren’t executing their program quite right. We tend now to think that many of the risk genes for psychiatric illnesses just introduce small biases in the programs of brain development. It’s not that they derail the brain completely. Even in someone with schizophrenia, most of the brain is functioning correctly. But these genetic flaws introduce glitches that interfere with how cells talk to their neighbors—and this can have devastating long-range consequences.”

Trained as both a neurologist and psychiatrist, Dr. Weinberger is known the world over as one of the first investigators to make a solid connection between irregularities in specific genes and the occurrence of specific psychiatric disorders. The aim of the research effort he leads at the Lieber Institute is to develop over time a finely detailed understanding of what is different, biologically and genetically, about the brains of people with psychiatric disorders vs. healthy people. The ultimate goal is to develop more targeted medications that effectively treat, prevent or cure psychiatric illnesses.
One approach at the Institute is to study curated, postmortem brains with molecular, genetic and cellular methods. The Lieber Institute has an unmatched collection of some 1,350 postmortem human brains, about 500 of them contributed by healthy people and the remainder by people who were diagnosed with depression, bipolar disorder, schizophrenia, panic disorder, obsessive-compulsive and post-traumatic stress disorders, as well as Alzheimer’s disease.

The large sample of curated brains—of people from the 10th week of gestation to age 90—provides a wealth of data about how brains work at the genetic and molecular level, across all stages of the life cycle.

Another line of work at the Institute is to transform donated skin cells into brain cells and “to make little brains in a dish,” Dr. Weinberger explains. “Our investigators are beginning to take these little neurons in a dish and put them in the context of other cell types found in the brain, and create actual circuits. Incredibly, these cells in a dish take on a life of their own; they have a ‘behavior.’ Cells in the dish, like cells in the brain, link up, communicate with one another.”

The insights in models such as this come from watching how neural cells grow and assemble—according to their genetic program—as a prelude to understanding what goes wrong in an actual brain, in someone who is ill.

Within 10 years, Dr. Weinberger posits, there will be enough knowledge to develop the next generation of psychiatric medications—ones, he says, “that will interfere with the things that faulty genes make brain cells do that we want them to stop doing.”

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